This application describes a five-year research career development program in the study of mechanisms of mitochondrial proliferation and function in mammalian cells. The research program will be carried out in the laboratory of Dr. Stephen Elledge, Professor of Genetics at Harvard Medical School. Dr. Elledge has successfully trained many academic scientists in the past. The candidate is a clinical fellow in Endocrinology, Diabetes, and Metabolism at Massachusetts General Hospital, and previously carried out Ph.D. research on glucose and lipid metabolism with Dr. Bruce Spiegelman at Dana-Farber Cancer Institute. The proposed research program will provide training in genetic approaches to analyzing regulatory pathways in mammalian cells, including gene silencing by RNA interference. The candidate will also acquire expertise in a number of genomics and bioinformatics methods. These experiences will complement the candidate's previous training in metabolism and will aid his development as an independent physician-scientist. To further enhance the training, an advisory committee of experts in mitochondrial biology, metabolism and molecular physiology, and mouse genetics will provide scientific and career advice. In a pilot study utilizing an RNAi-based genetic screen, the candidate has identified a zinc finger protein as a regulator of mitochondrial biogenesis and function in mammalian skeletal muscle cells. Preliminary evidence suggests that this protein is regulated in physiological contexts. The candidate intends to carry out further characterization of the effect of the protein on muscle cell mitochondrial number and activity. The molecular mechanism underlying the protein's effect will be investigated using a combination of biochemical, genetic, and cell biological approaches. In parallel, an expanded RNAi screen encompassing the entire genome will be carried out to obtain a global view of the regulatory pathways with particular emphasis on transcriptional networks. The Elledge lab provides a stimulating intellectual environment, broad technical expertise, and extensive scientific resources that reflect years of continuous innovation in the lab. It is an ideal setting for the candidate to develop professionally and to successfully launch his academic career as a physician-scientist. Relevance to public health (lay language): We aim to study the genes involved in mitochondrial proliferation and function. These studies may eventually help understand and treat diseases, such as type 2 diabetes, which are known to be characterized by abnormalities in mitochondrial number and function.